Black men suffer disproportionately from hypertension. Antihypertensive medication nonadherence is a major contributor to poor blood pressure control, yet few studies consider how psychosocial functioning may impact black men’s medication adherence. The authors examined the direct and mediating pathways between depressive symptoms, psychosocial stressors, and substance use on antihypertensive medication nonadherence in 196 black men enrolled in a clinical trial to improve hypertension care and control. The authors found that greater depressive symptoms were associated with more medication nonadherence (β=0.05; standard error [SE], 0.01; P<.001). None of the psychosocial stressor variables were associated with antihypertensive medication nonadherence. Alcohol misuse was associated with increased medication nonadherence (β=0.81; SE, 0.26; P<.01), but it did not mediate the association between depressive symptoms and medication nonadherence. Clinicians should consider screening for depressive symptoms and alcohol misuse if patients are found to be nonadherent and should treat or refer patients to appropriate resources to address those issues.